In certain instances numerous pharmacogenetic disorders in man cause individuals to react very differently to the same dose of the same drug. The teratogenic, carcinogenic, or toxic effects of certain drugs and other foreign compounds (xenobiotics) may also reflect important genetically mediated differences between individuals. Accordingly, our laboratory has developed experimental model systems for studying drug metabolism in cell culture and in a colony of inbred strains of mice. Also, by determining certain drug-metabolizing differences in cultured human lymphocytes, we hope to be able to predict genetic differences in the clinical response of certain drugs given to the patient. We have determined that the induction of at least 10 drug- metabolizing enzyme activities is regulated at one or two genetic loci, which we propose be designated Ah for aromatic hydrocarbon responsiveness. Expression of enzyme "induction" may segregate as an autosomal dominant or codominant trait, or the lack of induction may be expressed dominantly, depending on the inbred strains crossed. The relative presence of "aromatic hydrocarbon responsiveness" in certain mice results in more 3-methylcholanthrene-initiated tumors, in more rapid metabolism when given certain drugs, and in a shortened survival time when given various polycyclic hydrocarbons either orally or intraperitoneally. These genetically mediated dissimilarities in xenobiotic metabolism may be a useful probe in demonstrating differences in the rates of formation of certain drug-induced birth defects.